The present invention relates to a whole blood hollow fiber membrane filter medium including a ceramic material having a pore size ensuring permeability to the liquid part of whole blood, preferably to blood plasma or serum and its molecular components, but retaining blood cells and further relates to the use of said whole blood hollow fiber membrane filter medium for separating blood plasma or serum from whole blood.
In medical technology, various kinds of blood and plasma/serum separation and treatment processes are known and state of the art. The most common method for separating blood cells from the liquid part of the blood is centrifugation.
In transfusion medicine, filters are used to remove leucocytes from transfusion blood and to remove blood clots and particles. Furthermore, artery filters are applied during surgeries, e.g. to remove blood clots, particles and gas bubbles. Plasmapheresis filters are used to clean or to substitute plasma from patients, which is poisoned by bacteria, viruses or further components, which are life-threatening, with artificial blood plasma or plasma from donors.
Moreover, microdevices are known for whole blood analysis, which are either based on test stripes or on lab-on-a-chip technology. When using these devices, only a few microliters of blood are required for the blood or plasma/serum analysis. The separation of plasma/serum from whole blood is usually performed by fluid mechanical effects like the wetting behavior of different surfaces or the application of microchannels. Although this method is very attractive concerning the quick obtainment of blood analysis results, the results from these analyses are restricted to a few test-specific components. These applications are unable to replace a plasma/serum based blood analysis with the existing sophisticated systems in labs and hospitals, which comprise the analysis of a plurality of blood components and which are able to give an overall picture of a patient's state of health. Furthermore, the task of separating blood cells from the liquid part of the blood is also not yet solved satisfactorily for microdevices.
In many countries, it is obligatory to withdraw a sufficient amount of blood from the patients to be able to store the obtained plasma/serum sample for some time to check the analysis result some time later with a so-called retain sample. Until now, the task of obtaining enough cell-free plasma/serum can however only be accomplished by centrifugation.
The centrifugation procedures, which are typically used for separating blood plasma/serum from whole blood, are not only cumbersome requiring large amounts of manual and mechanical handling, but are also time consuming, which is particularly disadvantageous in emergency medicine.
Blood plasma/serum analysers, which have a great capacity for plasma/serum samples, cannot operate at full capacity when a centrifugation process is applied upstream, which works batch-wise and represents the »bottleneck« in blood sample processing. This bottleneck problem could possibly be overcome with a continuous filtration process instead of a centrifugation process for plasma/serum generation. Such a continous system would allow a flexible analysis of the samples: Urgent samples from emergency patients could be processed with a higher priority without any need of interrupting a running centrifugation process.
It is a further advantage of a simple filtration process for whole blood separation that the whole blood separation into plasma/serum and blood cells can be performed directly after collecting the whole blood sample. This is especially advantageous for the quality of the subsequent blood analysis as the red blood cell stability decreases with increasing sample storage time. This can influence the plasma/serum composition when the plasma/serum separation is not performed immediately after the blood sample withdrawal, but with some time delay. This aspect becomes important in rural areas or developing countries when there is no centrifuge available for the plasma/serum separation and when the blood sample has to be transported for a long period of time and/or distance, sometimes even in a hot and/or humid environment.
A subsequent whole blood separation into plasma/serum can be advantageous for point-of-care testing devices, which are used to provide a quick blood analysis at/near the patient to get a quick blood analysis result outside of a clinical laboratory to make immediate decisions about patient care. Typically point-of-care testing is performed by non-laboratory personnel. A quick foregoing plasma filtration process facilitates the quick blood analysis and enables new operating conditions for point-of-care devices, since most of them work with whole blood or with the aforementioned microdevices which lead to a very small yield of plasma/serum volume. The whole blood separation process can also be integrated within the point-of-care device.
Therefore, whole blood filtration methods have been developed as an alternative measure for obtaining blood plasma/serum from whole blood. These plasma/serum filtration methods known in the art are however problematic in view of e.g. the blood cell concentration, the plasma/serum yield, the molecular adsorbance capacity, the extent of hemolysis, and the leakage of blood cells (erythrocytes, thrombocytes and leukocytes). Hemolysis is one of the important problems because the red blood cells, if ruptured, will alter the concentration of some plasma/serum analytes required for further testing and, in some cases, make an analysis using optical measurements techniques impossible due to the red color of the released hemoglobin. Moreover, the leakage of blood cells is problematic because the cells or even other particles can damage the blood plasma/serum analyzers as the sensitive capillaries and conduits can become plugged. Only (substantially) cell- and hemolysis-free plasma/serum can be used for a reliable blood analysis.
Hollow fiber membrane devices permitting separation of blood plasma from whole blood without the need for a centrifugation have been used for plasma exchange therapy (PET)/apheresis. In PET, the separated plasma is eliminated and the separated blood cells with replacement fluids are returned to the patient. This hollow fiber membrane technology offers an alternative to centrifugation and conventional filtration techniques for bioseparation.
U.S. Pat. No. 5,674,394 discloses a small-volume disposable filtration technology to separate blood plasma from whole blood. The system for preparing said plasma comprises a single use filter unit having two inlets in fluid communication with each other, an outlet, and a filtration membrane selectively permeable to blood plasma separating the inlet from the outlet. Manually operable, single use pumps are connected to the inlets. A flow path is defined along the membrane between the pumps, whereby whole blood can be repeatedly exchanged between the two pumps, past the membrane, to cause plasma to flow through the membrane and out of the outlet.
U.S. Pat. No. 5,919,356 discloses a device for sampling a fluid, preferably a body fluid such as blood, the device having filtration means for separating components of the fluid, a conduit directing flow of the fluid to be sampled from a source through the device, and sensing means which can detect the presence of a component in the fluid.
US 2003/0206828 discloses a portable hand-held blood sampling device having a self-filling capability, which includes a blood separation filter. The filter has a plurality of pores sized to permit passage of selected blood constituents such as blood plasma through the device. The filter is a hollow fiber filter, which extends within and along a length of the tube, the filter being sealed at the first end thereof proximal to the inlet end and in fluid communication with the outlet end at a second end thereof.
A need remains for filter media for separating blood plasma/serum from whole blood, which allow for an effective separation of blood plasma/serum from whole blood and which are suitable for use in a quick, safe and robust way to get a suitable amount of cell-free plasma/serum, without causing hemolysis. With this kind of filtration process a deterioration of the blood quality after the blood withdrawal from the patient or bad analysis results due to a time delay in a centrifugation process or due to transportation will be avoided as the blood cell separation can be performed immediately without a centrifuge in an emergency case or at the point of collection of the blood sample.
It is therefore an object of the present invention to provide a whole blood hollow fiber membrane filter medium for separating blood plasma/serum from whole blood, which is advantageous over the prior art, in particular regarding the problems of hemolysis and leakage of blood cells (erythrocytes, thrombocytes and leukocytes).
It is another object of the present invention to provide a whole blood hollow fiber membrane filter medium, which can be used for separating blood plasma/serum from a whole blood sample, e.g. by cross-flow filtration, wherein the separation of a sufficient amount of cell-free blood plasma/serum is possible with no or substantially no hemolysis.
Additionally, it is an object of the present invention to provide a whole blood hollow fiber membrane filter medium, which can be used for separating blood plasma/serum from a whole blood sample, wherein the material and the surface properties of the filter medium are chosen in such a manner that hemolysis due to the contact between the whole blood sample and the hollow fiber membrane filter medium is reduced or avoided. That means that negative effects like pH-shifts, osmotic changes or capillary effects caused by the porous membrane structure are reduced.
It is yet another object of the present invention to provide a whole blood hollow fiber membrane filter medium, which can be used for separating blood plasma/serum from a whole blood sample, wherein the separation of blood plasma/serum is possible, preferably in a manual way or in an easy automatic way without using centrifugation means.
It is another object of the present invention to provide a whole blood hollow fiber membrane filter medium, which can be used for separating blood plasma/serum from a whole blood sample, wherein the separation is less time consuming than the separation with conventional methods such as centrifugation methods.
It is another object of the present invention to provide a whole blood hollow fiber membrane filter medium, which can be used for separating blood plasma/serum from a whole blood sample. It should be noted in this regard that there is typically no need that the blood cells are recovered so that the whole blood hollow fiber membrane filter medium containing the blood cells can be used as a medical disposable.
It is another object of the present invention to provide a whole blood hollow fiber membrane filter medium, which can be used for separating blood plasma/serum from a whole blood sample, and which is suitable for multiple use.
It is another object of the present invention to provide a whole blood hollow fiber membrane filter medium, which can be used for separating blood plasma/serum from an urgent whole blood sample in an emergency case. Ideally, the cell separation can already take place at the scene of blood withdrawal. Subsequently the obtained plasma/serum sample can be immediately processed and can be directly delivered into the blood plasma/serum analyzer, e. g. a point-of-care testing device. The term emergency case comprises not only patient diagnosis in case of accidents, but also all blood treatment processes as they are provided by medical offices or patient control during surgeries in hospitals. In this regard, it is also an object to overcome the bottleneck problem of centrifugation and/or to avoid a falsification of the blood analysis due to a long treatment or transport of the unseparated whole blood sample.
It is another object of the present invention to provide a whole blood hollow fiber membrane filter medium, which can be used for separating blood plasma/serum from a whole blood sample without clogging of the filter medium.
It is another object of the present invention to provide a whole blood hollow fiber membrane filter medium, which can be used for separating blood plasma/serum from a whole blood sample, wherein the whole blood hollow fiber membrane filter medium does not induce rupture of blood cells e.g due to frictional forces or other mechanical stresses.
It is another object of the present invention to provide a whole blood hollow fiber membrane filter medium, which can be used for separating blood plasma/serum from a whole blood sample and reduces the risk of a leakage of red blood cells into the filtrate.
It is another object of the present invention to provide a whole blood hollow fiber membrane filter medium, which is suitable for providing a blood cell containing concentrate with which further testing is possible if desired.
It is another object of the present invention to provide a whole blood hollow fiber membrane filter medium which leads to a cell-free or substantially cell-free plasma/serum as a filtrate, wherein the relative amounts of the molecular components to be analyzed remain substantially unchanged upon filtration. Ideally, the whole blood hollow fiber membrane filter medium is inert and hemocompatible, releases no extractables or particles, and neither leads to the adsorption of particular blood plasma/serum components on its solid surface nor to a cross-reaction of particular blood plasma/serum components with its solid surface.